The epidermal growth factor receptor (EGFR/ErbB) family of receptor tyrosine kinases (RTKs) includes four family members in humans: EGFR (HER1, ErbB1), HER2 (ErbB2, Neu), HER3 (ErbB3), and HER4 (ErbB4). Each family member consists of an extracellular ligand-binding region, a single membrane-spanning region, a cytoplasmic tyrosine kinase, and a C-terminal tail of ~230 amino acids. All EGFR/ErbB family members are essential for normal embryonic development, and abnormal activity of each ErbB has been associated with human cancer. In particular, overexpressed or active EGFR and HER2 are associated increased severity of lung, colon, and head-and-neck cancers (EGFR) or breast cancer (HER2), and several drugs targeting EGFR and HER2 are FDA-approved anticancer therapies. The canonical model of vertebrate EGFR activity is that ligand binding to the extracellular region stabilizes a specific dimeric conformation of the receptor that in turn drives the kinase domain into an asymmetric dimer in which its activity is stimulated. The activated kinase then phosphorylates several sites in the receptor C-tail as well as other substrates, which results in changes in the localization and/or activity of downstream effectors and initiation of signaling cascades that alter cell growth and differentiation. Much has been learned about the mechanisms governing ErbB activity from X-ray structural studies of ErbB fragments, which have also had a large impact on the design and understanding of ErbB-targeted therapeutics, but several key questions remain. For example, differences in the structure and behavior of Drosophila and vertebrate EGFRs appeared to suggest fundamentally different activation mechanisms for these receptors including the presence of a 1:2 ligand:EGFR signaling complex in Drosophila. A vertebrate 1:2 ligand:EGFR complex seemed ruled out by the symmetric 2:2 ligand:EGFR complexes observed in crystals of vertebrate EGFR:ligand complexes and the presence of an autoinhibited (and apparently dimerization incompetent) conformation of vertebrate ErbBs in the absence of ligand. Recent results from my laboratory suggest that a 1:2 ligand:EGFR complex also exists for vertebrate ErbBs, however, and we propose (i) to confirm the existence of this 1:2 complex and probe its structure using both X-ray structural and cell-based functional studies. The presence of a 1:2 ligand:receptor complex for vertebrate ErbBs would resolve what seemed to be different behavior of Drosophila and vertebrate ErbB extracellular regions, and we propose (ii) to investigate whether the Drosophila kinase regions are governed by a vertebrate-like "asymmetric dimer" mechanism. The ErbB-related type I insulin-like growth factor receptor also mediates key cellular processes, and we propose (iii) to initiate structural studies of this receptor to understand how ligand binding regulates its activity and its relationship to ErbB mechanisms. These studies will establish a molecular basis for understanding of the physiological properties of these key receptors and illuminate new or optimal strategies to target their function in disease states. PUBLIC HEALTH RELEVANCE: The epidermal growth factor receptor (EGFR/ErbB) family of receptor tyrosine kinases comprises four members in humans, each of which is essential for normal development and has been associated with human cancers. Abnormal activity of family members EGFR and HER2 in particular are associated with increased cancer severity and is the target of several FDA-approved anticancer drugs. By studying the molecular mechanisms governing the activity of these and related receptors we will gain important insight into how these receptors mediate their normal biological activities, how regulation of their activity breaks down in disease, and what molecular strategies are likely to best inhibit activated forms of these receptors.